This invention relates to pyrazole derivatives useful in the treatment of a variety of conditions mediated by endothelin and to pharmaceutical formulations containing such compounds useful for the treatment of humans and non-human mammals.
Endothelin (ET) is a potent vasoconstrictor synthesised and released by endothelial cells. There are three distinct isoforms of ET:ET-1, ET-2 and ET-3, all being 21-amino acid peptides and herein the term xe2x80x98endothelinxe2x80x99 refers to any or all of the isoforms. Two receptor subtypes, ETA and ETB have been pharmacologically defined (see for example H. Arai et al., Nature, 348, 730, 1990) and further subtypes have recently been reported. Stimulation of ETA promotes vasoconstriction and stimulation of ETB receptors causes either vasodilation or vasoconstriction. The main effects of ET are observed in the cardiovascular system, particularly in the coronary, renal, cerebral and mesenteric circulation, and the effects of endothelin are often long-lasting. Stimulation of ET receptors also mediate further biological responses in cardiovascular and non-cardiovascular tissues such as cell proliferation and matrix formation.
Increased circulating levels of endothelin have been observed in patients who have undergone percutaneous transluminal coronary angioplasty (PTCA) (A. Tahara et al., Metab. Clin. Exp. 40, 1235, 1991) and ET-1 has been found to induce neointimal formation in rats after balloon angioplasty (S. Douglas et al., J. Cardiovasc. Pharm., 22 (Suppl 8), 371, 1993). The same workers have found that an endothelin antagonist, SB-209670, causes a 50% reduction in neointimal formation relative to control animals (S. Douglas et al., Circ Res, 75, 1994). Antagonists of the endothelin receptor may thus be useful in preventing restenosis post PTCA. The ETA/B receptor antagonist Bosentan reportedly decreased blood pressure in hypertensive patients (H. Krum et al., New Eng. J. Med. (1998) 338, 784-790). Antagonists of ETB receptors such as BQ-788 have been demonstrated to increase peripheral resistance in man (Hypertension (1999) 33, 581-585). Thus ETA-selective receptor antagonists are most likely to be of benefit in hypertension.
Endothelin-1 is produced in the human prostate gland and endothelin receptors have been identified in this tissue (Y. Saita et al., Eur. J. Pharmacol. (1988) 349, 123-128). Since endothelin is a contractile and proliferative agent, endothelin antagonists could be useful in the treatment of benign prostate hypertrophy.
There is widespread localisation of endothelin and its receptors in the central nervous system and cerebrovascular system (R. K. Nikolov et al., Drugs of Today, 28(5), 303, 1992) with ET being implicated in cerebral vasospasm, cerebral infarcts, septic shock, myocardial infarction and neuronal death.
Elevated levels of endothelin have also been observed in patients with:
recurrent airway obstruction (Pulm. Pharm. Ther. (1998) 11:231-235);
asthma (Am. J. Resp. Crit. Care Med., (1995) 151:1034-1039);
acute renal failure (K. Tomita, et al., Med. Philos. (1994) 13(1), 64-66);
chronic renal failure (F. Stockenhuber et al., Clin Sci (Lond.), 82, 255, 1992);
ischaemic Heart Disease (M. Yasuda, Am. Heart J., 119, 801, 1990);
stable or unstable angina (J. T. Stewart, Br. Heart J., 66, 7 1991);
pulmonary hypertension (D. J. Stewart et al., Ann. Internal Medicine, 114, 464, 1991);
congestive heart failure (R. J. Rodeheffer et al., Am. J. Hypertension, 4, 9A, 1991);
preeclampsia (B. A. Clark et al., Am. J. Obstet. Gynecol., 166, 962, 1992);
diabetes (A. Collier et al., Diabetes Care, 15 (8), 1038, 1992);
Crohn""s disease (S. H. Murch et al., Lancet, 339, 381, 1992); and
atherosclerosis (A. Lerman et al., New Eng. J. Med., 325, 997, 1991).
In every case the disease state associated with the physiologically elevated levels of endothelin is potentially treatable with a substance which decreases the effect of endothelin, such as an endothelin receptor antagonist, or a compound which binds endothelin such that it reduces the effective concentration thereof at the endothelin recepotors.
Compounds that antagonise the ETA receptor to a greater extent than the ETB receptor are preferred as ETA receptors are predominantly present in vascular smooth muscles. Blockade of ETB receptor activation may reverse endothelial dependent vasodilation which is beneficial in hypertension. ET may also mediate regeneration of damaged tissue via the ETB receptor, such as proximal tubule cells in the kidney. Thus blockade of ETB receptors, e.g. with a non-selective ET antagonist could inhibit tissue repair. ETB receptors are also involved in the clearance of ET from the systemic circulation. Increased levels of ET are generally considered detrimental. Rises in circulating levels have been observed with non-selective ET antagonists. Treatment with selective ETA receptor antagonists are not likely to induce such rises in circulating levels.
There are a number of publications relating to N-(pyrimidin-4-yl)sulphonamide derivatives having endothelin binding/antagonist activity, for example EP-A-0743307, EP-A-0658548, EP-A-0633259, EP-A-0882719, WO-A-96/20177, EP-A-0801062, WO-A-97/09318, EP-A-0852226, EP-A-0768304, WO-A-96/19459, WO-A-98/03488 and EP-A-0713875.
International Patent Application publication number WO-A-96/19455 discloses phenyl and pyridin-4-yl sulphonamides as endothelin antagonists.
International Patent Application publication number WO-A-97/11942 discloses various (4-arylthioisoxazol-3-yl)sulphonamides, with an aldehyde moiety linked to the 5-position of the isoxazole ring, as selective ETB receptor selective antagonists.
We have unexpectedly found that pyrazoles of formulae IA and IB below have good affinity for endothelin receptors, and are selective for ETA over ETB.
According to the present invention, there are provided compounds of formulae IA and IB: 
Wherein
R1 is H, C1-6 alkyl (optionally substituted by one or more halo, OR4 or NR4R5 groups), C2-6 alkenyl (optionally substituted by one or more halo groups), C2-6 alkynyl (optionally substituted by one or more halo groups), C(O)R4, CO2R4, CH2aryl4, CONR4R5, aryl4 or het1,
R2 is C1-6 alkyl, cyclopropylmethyl, or CH2CH2OG where G is H, C1-6 alkyl (optionally substituted by a C3-6 cycloalkyl group), C(O)R4, CONHAr2 or Ar2,
R4 and R5 are each independently H or C1-6 alkyl (optionally substituted by one or more halo groups),
X is a direct link O, S, SO, SO2, CO or CH2,
R3 is
a) a C6-14 aromatic hydrocarbon group; or
b) an optionally benzo-fused 5- or 6-membered heterocyclic group with one to three hetero-atoms atoms in the heterocyclic ring, which hetero-atoms are independently selected from N, O and S; or
c) CH2CH2Ph, CH:CHPh; or
d) C1-6 alkyl, optionally substituted by 1-4 substituents selected from: halo, C1-6 alkoxy, CO2R4, OC(O)R4 and NR4R5,
each of which groups (a), (b) and (c) is optionally substituted by up to four substituents independently selected from:
i) C1-6 alkyl, optionally substituted by 1-4 substituents selected from: halo, OR4, CO2R4, OC(O)R4 and NR4R5;
ii) C1-6 alkoxy;
iii) CO2R4 and OC(O)R4;
Halo;
NO2;
vi) CN;
NR4R5;
C1-3 alkylenedioxy;
OH;
Alkoxy carbonyl;
Ar1 and Ar2 are each independently aryl5 or het1 
aryl4 is a phenyl or naphthyl group optionally substituted by up to three substituents independently selected from C1-3 alkyl, CF3, halogen, C1-3 alkoxy, CF1-3O, OH, NO2, CN, NR4R5, COR4, CO2R4, CONR4R5, S(O)p(C1-3 alkyl), CH2NR4R5, NR4COR5, COCF3, CH2OH, S(O)pCF3, C(xe2x95x90NH)NH2,
aryl5 is a phenyl, 1,3-benzodioxyl or naphthyl group optionally substituted by up to three substituents independently selected from C1-3 alkyl, CF3, halogen, C1-3 alkoxy, OCF3, OH, NO2, CN, NR4R5, C(O)R4, CO2R4, CONR4R5, S(O)p(C1-3 alkyl), CH2NR4R5, NR4COR5,COCF3, CH2OH S(O)pCF3, C(xe2x95x90NH)NH2, C2-3 alkynyl, C2-3 alkenyl, phenyl and het2,
het1 is a 5- to 7-membered heterocyclic group with one to three hetero-atoms in the heterocyclic ring,
which hetero-atoms are independently selected from N, O and S,
which heterocyclic ring is optionally benzo-fused, which group may be fully saturated or partially or fully unsaturated, and which is optionally substituted by up to three substituents independently selected from C1-3 alkyl, CF3, halogen, C1-3 alkoxy, CF3O, OH, NO2, CN, NR4R5, COR4, CO2R4, CONR4R5, S(O)p(C1-3 alkyl), CH2NR4R5, NR4COR5, COCF3, CH2OH, S(O)pCF3, C(xe2x95x90NH)NH2, C2-3 alkynyl, C2-3 alkenyl, phenyl and het2, and, when present in the G moiety, is linked to the O atom to which it is joined to the remainder of the compound of formula (IA) or (IB) via a carbon atom in said het1 group,
het2 is a 5- to 7-membered heterocyclic group with one to three hetero-atoms in the heterocyclic ring,
which hetero-atoms are independently selected from N, O and S,
which group may be fully saturated or partially or fully unsaturated,
and p is 0, 1 or 2,
and pharmaceutically acceptable derivatives thereof, hereinafter referred to as the xe2x80x9csubstances of the inventionxe2x80x9d.
Pharmaceutically acceptable derivatives include those compounds in which the functional groups explicitly recited above have been derivatised to provide prodrugs which can be converted to the parent compound in vivo. Such prodrugs are discussed in Drugs of Today, Vol 19, 499-538 (1983) and Annual Reports in Medicinal Chemistry, Vol 10, Ch 31 p306-326. In addition, pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, such as alkali metal salts (for example sodium salts) of any acidic groups that may be present. Also included are zwitterionic species which may exist.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19, 1977.
Halo includes fluoro, chloro, bromo and iodo groups.
Alkyl, alkenyl and alkynyl groups may be straight chain, branched or cyclic where the number of carbon atoms allows.
A C6-14 aromatic hydrocarbon group may include such groups as phenyl, naphthyl, indenyl, anthryl and phenanthryl.
In one embodiment of the invention, R1 is H, C1-6 alkyl (optionally substituted by one or more halo, OR4 or NR4R5 groups), C2-6 alkenyl (optionally substituted by one or more halo groups), C2-6 alkynyl (optionally substituted by one or more halo groups), CO(C1-6 alkyl optionally substituted by one or more halo groups), CO2(C1-6 alkyl optionally substituted by one or more halo groups), CONR4R5, aryl4 or het1,
Preferably R1 is H, CH3, CH2Ph, CH2CH2OH.
More preferably R1 is H, CH3.
Most preferably R1 is CH3.
In one embodiment of the invention, R2 is CH2CH2OG where G is H or Ar2,
Preferably R2 is CH3, cyclopropylmethyl, CH2CH2OG, wherein G is H, Ph, C(O)CH3, C1-2 alkyl, N-(2-pyridyl)aminocarbonyl, 4-fluorophenyl or pyrimidin-2-yl, said pyrimidin-2-yl optionally substituted at the 5 position by F, Cl, Br, CH3, CH2OH, C(O)H, SO2CH3, NO2, NH2, SCH3, S(O)CH3, furan-2-yl or thien-2-yl.
More preferably R2 is CH2CH2OG, wherein G is Et or pyrimidin-2-yl, said pyrimidin-2-yl optionally substituted at the 5 position by Cl, Br, CH2OH, SO2CH3, SCH3, S(O)CH3 or thien-2-yl. Most preferably R2 is CH2CH2OG, wherein G is pyrimidin-2-yl, said pyrimidin-2-yl optionally substituted at the 5 position by Cl, Br.
In one embodiment, R3 is a phenyl group or an optionally benzo-fused 5- or 6-membered heterocyclic group with one to three hetero-atoms in the heterocyclic ring, which hetero-atoms are independently selected from N, O and S, each of which groups is optionally substituted by up to three substituents independently selected from halogen, C1-6 alkyl (optionally substituted by OH, halo, NR4R5 or CO2R4), CN, OC1-6 alkyl (optionally substituted by one or more halogen) and CO2R4.
Preferably R3 is
a) phenyl; or
b) an optionally benzo-fused 5- or 6-membered heterocyclic group with one to three hetero-atoms in the heterocyclic ring, which hetero-atoms are independently selected from N, O and S; or
c) CH2CH2Ph, CH:CHPh
each of which groups (a) and (b) is optionally substituted by up to three substituents independently selected from:
i) halo,
ii) C1-6 alkyl optionally substituted by OH, halo, NR4R5 or CO2R4,
iii) CN,
iv) O(C1-6 alkyl optionally substituted by one or more halogen) and
v) OC(O)R4 and CO2R4,
and group (c) is optionally substituted by 1-3 substituents selected from H, halo and C1-6 alkyl.
More preferably R3 is
a) Phenyl, optionally substituted at the 4 position by: CH(CH3)2, C(CH3)3, C(CH3)2CO2Et, C(CH3)2CO2H, C(CH3)2CH2OH, C(CH3)2CH2OC(O)CH3, Cl, Br, I CH3O, CF3, C(CH3)2CH2CH3;
b) Pyrid-2-yl, optionally substituted at the 5 position by CH(CH3)2, CH3 or CH(CH3) CH2OH;
c) CH2CH2Ph, CH:CHPh, said Ph groups optionally substituted by H, halo or C,1-3 alkyl.
Yet more preferably R3 is
a) Phenyl, optionally substituted at the 4-position by: C(CH3)3, C(CH3)2CO2H, C(CH3)2CH2OH, C(CH3)2CH2OC(O)CH3C(CH3)2CH2CH3;
b) Pyrid-2-yl, substituted at the 5 position by CH(CH3)CH2OH;
c) CH2CH2Ph, CH:CHPh, said Ph groups optionally substituted by H, Cl or C1-2 alkyl.
Most preferably R3 is
a) Phenyl, substituted at the 4 position by: C(CH3)3, C(CH3)2CO2H, C(CH3)2CH2OH, C(CH3)2CH2OC(O)CH3;
b) Pyrid-2-yl, substituted at the 5 position by CH(CH3)CH2OH;
c) CH2CH2Ph, CH:CHPh.
Preferably X is a direct link or O.
More preferably X is a direct link.
Preferably Ar1 is
a) Phenyl, optionally substituted at the 4 position by: CF3, CN, vinyl, C(O)CH3, OCF3, COOH, F, Cl, OCH3, CH2OH, CH3;
b) 3,4-dihydroxyphenyl, 3,4-dimethoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-chlorophenyl, benzo[b]thien-2-yl, 1,3-benzodiox-5-yl.
More preferably Ar1 is
a) Phenyl, optionally substituted at the 4 position by F, Cl, OCH3, CH2OH or CH3;
b) 3,4-dimethoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 1,3-benzodiox-5-yl.
Most preferably Ar1 is
a) Phenyl, substituted at the 4 position by CH2OH or CH3;
b) 1,3-benzodiox-5-yl.
Preferably R4 and R5 are H and C1-3 alkyl (optionally substituted by one or more halo groups).
More preferably R4 and R5 are C1-3 alkyl.
Most preferably R4 and R5 are CH3.
Preferably Ar2 is a phenyl or pyrimidyl group optionally substituted by up to three substituents independently selected from C1-3 alkyl, CF3, halogen, C1-3 alkoxy, CF3O, OH, NO2, CN, NH2, CHO, CO2H, CONH2, S(O)p(C1-3 alkyl), thienyl and furyl.
More preferably Ar2 is phenyl, 5-bromopyrimid-2-yl, 5-nitroopyrimid-2-yl, 5-aminopyrimid-2-yl, 5-formylpyrimid-2-yl, 5-methoxypyrimid-2-yl, 5-chloropyrimid-2-yl, 5-(thien-2-yl)pyrimid-2yl, 5-(furan-2-yl)pyrimid-2-yl, pyrimid-2-yl, 5-fluoropyrimid-2-yl, 5-methylthiopyrimid-2-yl, 5-methylsulphonylpyrimid-2-yl or 5-methylsulphoxypyrimid-2-yl.
Most preferably Ar2 is 5-bromopyrimid-2-yl.
A preferred group of compounds are selected from the Examples and pharmaceutical derivatives thereof.
A more preferred group of compounds are:
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-4-(tert-butyl)benzenesulfonamide
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-4-(tert-butyl)benzenesulphonamide
N-[4-(1,3-benzodioxol-5-yl)-1-methyl-3-(2-{[5-(methylsulfonyl)-2-pyrimidinyl]oxy}ethoxy)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy-1-methyl-1H-pyrazol-5-yl)-1-methyl-1H-imidazole-4-sulfonamide
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-4-(2-hydroxy-1,1-dimethylethyl)benzenesulfonamide
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)benzenesulfonamide
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-1-methyl-1H-imidazole-4-sulfonamide
N-[4-(1,3-benzodioxol-5-yl)-3-(2-{[5-(methylsulfonyl)-2-pyrimidinyl]oxy}ethoxy)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide
N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-pentyl)benzenesulfonamide
2-[4-({[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]amino}sulfonyl)phenyl]-2-methylpropanoic acid
N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(2-hydroxy-1,1-dimethylethyl)benzenesulfonamide
N-[3-(2-ethoxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(2-hydroxy-1,1-dimethylethyl)benzenesulfonamide
N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide
4-(tert-butyl)-N-[3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide
4-(tert-butyl)-N-[3-{2-[(5-methylthio-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide
4-(tert-butyl)-N-[1-methyl-4-(4-methylphenyl)-3-{2-[(5-methylsulfinyl-2-pyrimidinyl)oxy]ethoxy}-1H-pyrazol-5-yl]benzenesulfonamide
4-(tert-butyl)-N-[1-methyl-4-(4-methylphenyl)-3-{2-[(5-methylsulfonyl-2-pyrimidinyl)oxy]ethoxy}-1H-pyrazol-5-yl]benzenesulfonamide
4-tert-butyl-N-[3-(2-{[2-(hydroxymethyl)-5-pyrimidinyl]oxy}ethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide
N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-4-(4chlorophenyl)-1-methyl-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide
N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-4-(4-methoxyphenyl)-1-methyl-1H-pyrazol-5yl]-4-(tert-butyl)benzenesulfonamide
4-(tert-butyl)-N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy}ethoxy}-4-(3-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl-benzenesulphonamide
4-(tert-butyl)-N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-4-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrazol-5-yl]-4-benzenesulphonamide
N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide
N-{3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-4-[4-(hydroxymethyl)phenyl]-1-methyl-1H-pyrazol-5-yl}-4-(tert-butyl)benzenesulfonamide
N-{3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-4-[4-(hydroxymethyl)phenyl]-1-methyl-1H-pyrazol-5-yl}4-(2-hydroxy-1,1-dimethylethyl)benzenesulfonamide
N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-carboxymethylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl hydroxy)benzenesulfonamide
2-[4-({[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]amino}sulfonyl)phenyl]-2-methylpropyl acetate
N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide
5-isopropyl-N-[1-methyl-4-(4-methylphenyl)-3-(2-{[5-(methylsulfonyl)-2-pyrimidinyl]oxy}ethoxy)-1H-pyrazol-5-yl]-2-pyridinesulfonamide
N-[3-(2-{[5-(hydroxymethyl)-2-pyrimidinyl]oxy}ethoxy)-1-methyl-4-(4-methylphenyl)-1-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-5-isopropyl-2-pyridinesulfonamide
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-5-(2-hydroxy-1-methylethyl)-2-pyridinesulfonamide
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-5-isopropyl-2-pyridinesulfonamide
N-[4-(1,3-benzodioxol-5-yl)-1-methyl-3-(2-{[5-(methylsulfonyl)-2-pyrimidinyl]oxy}ethoxy)-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide
N-[4-1,3-benzodioxol-5-yl)-3-{2-[(5-brompyrimidin-2-yl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl]-2-pyridine sulphonamide
N-[4-1,3-benzodioxol-5-yl)-3-{2-[(5-chloropyrimidin-2-yl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl]-2-pyridine sulphonamide.
Most preferred are the compounds:
N-[4-(1,3-benzodioxol-5-yl)-1-methyl-3-(2-{[5-(methylsulfonyl)-2-pyrimidinyl]oxy}ethoxy)-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-5-(2-hydroxy-1-methylethyl)-2-pyridinesulfonamide
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-4-(tert-butyl)benzenesulfonamide
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-4-(2-hydroxy-1,1-dimethylethyl)benzenesulfonamide
N-[4-(1,3-benzodioxol-5-yl)-3-(2-{[5-(methylsulfonyl)-2-pyrimidinyl]oxy}ethoxy)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide
2-[4-({[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]amino}sulfonyl)phenyl]-2-methylpropanoic acid
N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(2-hydroxy-1,1-dimethylethyl)benzenesulfonamide
N-[3-(2-ethoxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(2-hydroxy-1,1-dimethylethyl)benzenesulfonamide
4-(tert-butyl)-N-[3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide
4-(tert-butyl)-N-[1-methyl-4-(4-methylphenyl)-3-{2-[(5-methylsulfonyl-2-pyrimidinyl)oxy]ethoxy}-1H-pyrazol-5-yl]benzenesulfonamide
N-{3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-4-[4-(hydroxymethyl)phenyl]-1-methyl-1H-pyrazol-5-yl}-4-(tert-butyl)benzenesulfonamide
N-{3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-4-[4-(hydroxymethyl)phenyl]-1-methyl-1H-pyrazol-5-yl}-4-(2-hydroxy-1,1-dimethylethyl)benzenesulfonamide.
The substances of the invention may possess one or more chiral centres and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present invention. Racemic substances may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. In addition, chiral intermediates may be resolved and used to prepare chiral compounds of formulae IA and IB.
The substances of the invention are useful because they blockade ET receptors and are thus useful in the treatment or prevention of any diseases for which such a blockade is beneficial. More particularly, they are useful in the treatment and prevention of restenosis, acute/chronic renal failure, hypertension including pulmonary and systemic hypertension; benign prostatic hypertrophy, male erectile dysfunction, prostate cancer, metastatic bone cancer, congestive heart failure, stroke, subarachnoid haemorrhage, angina, atherosclerosis, cerebral and cardiac ischaemia, prevention of ischaemia/reperfusion injury (e.g. allografts), cyclosporin induced nephrotoxicity, glaucoma, radiocontrast nephropathy, diabetic neuropathy, allergy, restoration of organ perfusion in haemorrhagic shock, lipoprotein lipase related disorders, chronic obstructive pulmonary disease and hyaline membrane disease in newborn. The treatment of restenosis, renal failure and systemic and pulmonary hypertension are of particular interest. The substances of the invention may be administered alone or as part of a combination therapy.
The invention further provides Methods for the production of substances of the invention, which are described below and in the Examples and Preparations section. The skilled man will appreciate that the substances of the invention could be made by methods other than those herein described, by adaptation of the methods herein described and/or adaptation of a plethora of methods known in the art. It is to be understood that the synthetic transformation methods specifically mentioned herein may be carried out in various different sequences in order that the desired substances can be efficiently assembled. The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for synthesis of a given target substance.
It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a substance of the invention. This may be achieved by conventional techniques, for example as described in xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by T W Greene and P G M Wuts, John Wiley and Sons Inc, 1991.
In the Methods below, unless otherwise specified, the substituents are as defined above with reference to the compounds of formula (I) above.
Method 1
Compounds of formulae IA and IB can be made via reaction of the corresponding compounds of formula IIA or IIB as appropriate 
where P1 is a nitrogen protecting group, by deprotection of said nitrogen-protecting group with a suitable reagent and under suitable conditions. A suitable example of such a protecting group is the 2-methoxyethoxymethyl group, which can be removed by treatment with acidic ethanol at elevated temperature, as exemplified in Example 12 below.
Compounds of formulae IIA and IIB may be made via conventional methods as exemplified in the Preparations section below, see for instance Preparation 1.
Method 2
Compounds of formulae IA and IB where R2 is CH2CH2OH may be made via hydrolysis of the corresponding ester of formula IIIA or IIIB: 
wherein E is (C1-4 alkyl)CO, for example by treatment with aqueous base such as aqueous sodium hydroxide or aqueous potassium carbonate, in a suitable solvent such as methanol or ethanol. This type of reaction is exemplified in Examples 2, 52 and 78 below.
Compounds of formulae IIIA and IIIB may be made via conventional methods as exemplified in the Preparations section below (see for instance Preparation 4).
Method 3
Compounds of formulae IA and IB where R2 is CH2CH2OG and where G is Ar2 can be made from the corresponding compound of formulae IA or IB where G is H, for instance via reaction of the compound of formula IA or IB where G is H with a reagent of formula xe2x80x9cAr2xe2x80x94Lxe2x80x9d, where xe2x80x9cLxe2x80x9d is a suitable leaving group such as a halo, arenesulphonate, C1-4 alkanesulphonate or perfluoro(C1-4 alkane)sulphonate ion, suitably a chloride, phenylsulphonate, p-toluenesulphonate or mesylate ion, suitably in the presence of a base such as sodium hydride or potassium carbonate, in a suitable inert organic solvent such as N,N-dimethylformamide (DMF) or tetrahydrofuran (THF).
Preferably, Ar2 is 5-chloro-pyrimidin-2-yl or 5-bromo-pyrimidin-2-yl.
This type of reaction is mentioned in for example U.S. Pat. No. 5,728,706 and Tetrahedron (1984) 40, 1433, and is exemplified below in Examples 3, 4, 5, 9, 11, 13, 14, 16, 18, 20, 22, 24, 26, 28, 31, 33, 34, 36, 41, 42, 44, 45, 48, 49, 51, 53, 68, 69, 80, 91, 92, 93, 94, 95, 97, 103 and 109 and the same type of transformation is disclosed in Preparation 27.
Method 4
Compounds of formulae IA and IB can be made via reaction of the corresponding compound of formula IVA or IVB as appropriate, 
where L2 is a leaving group such as Cl, Br, I or triflate, P2 is H, R3SO2 or a nitrogen-protecting group such as methoxymethyl, iso-butoxycarbonyl, etc., and E is G as defined with reference to compounds of formulae IA and IB above, or E is a suitable oxygen-protecting group such as (C1-4 alkyl)CO (which protecting groups may be removed during the reaction or subsequent to it), with a reagent which is equivalent to a xe2x80x9cAr1xe2x80x94X31 xe2x80x9d synthon.
For instance where X is a direct link, the reagent which acts as the xe2x80x9cAr1xe2x80x94Xxe2x88x92xe2x80x9d synthon can be an organometallic species such as an arylboronic acid Ar1xe2x80x94B(OH)2, and aryltin species Ar1xe2x80x94SnBu3, an arylzinc species Ar1xe2x80x94ZnCl. Such reagent types are well known in the art as are the reaction conditions, catalysts, co-reagents, solvents, etc.
This type of reaction is exemplified in Examples 10, 30, 32 and 96 below, and the same reaction-site transformation is described in Preparations 13, 16, 18, 20 and 22.
Compounds of formulae IVA and IVB may be made via conventional methods as exemplified in the Preparations section below.
Method 5
Compounds of formulae IA and IB can be made via reaction of the corresponding compound of formula VA or VB as appropriate 
with a reagent R3xe2x80x94SO2xe2x80x94L3 where (L3)xe2x88x92 is a suitable leaving group such as a halogen, particularly chloride, under standard N-sulphonylation conditions, such as those exemplified in Examples 8, 40, 43, 47, 50, 59, 60, 61, 63, 64, 65, 66, 67, 75, 105 and 107. The same type of reaction is also used in Preparations 1, 4, 9, 23, 25 and 29.
Compounds of formulae VA and VB may be made via conventional methods as exemplified in the Preparations section below, e.g. Preparation 5.
Method 6
Compounds of formulae IA and IB where R2 is CH2CH2OG, where G is CONHaryl5 can be made from the corresponding compound of formulae IA or IB where G is H (Method 2), via reaction of the compound of formula IA or IB where G is H, with a reagent of formula xe2x80x9caryl5xe2x80x94CO2Hxe2x80x9d, in the presence of an aryl substituted phosphoryl azide, suitable base such as triethylamine, 4-dimethylaminopyridine and a suitable inert organic solvent such as toluene at a temperature of 0-100xc2x0 C., preferably a temperature of 35-40xc2x0 C.
This type of reaction is mentioned below in Example 57.
Method 7
Compounds of formulae IA and IB where R1 is CH2CH2OH can be made via reaction of the corresponding compounds of formula VIA or VIB as appropriate 
where P1 is H, or a suitable N protecting group such as methoxy methyl group and P3 is a suitable hydroxy protecting group such as CO(C1-4 alkyl) or a silyl optionally substituted with C1-4 alkyl and/or phenyl groups and treated with a suitable acid such as oxalic acid, as exemplified in Example 81 or a suitable fluoride source such as tetrabutyl ammonium fluoride as exemplified in Example 39. Compounds of formulae VIA and VIB may be made via conventional methods as exemplified in the Preparations section below, see for instance Preparations 27 and 54.
Method 8
Compounds of formulae IA and IB where R1 is H can be made via reaction of the corresponding compounds of formula VIIA or VIIB as appropriate 
where P4 a suitable protecting group such as a benzyl group and is treated under suitable hydrogenolysis conditions in a suitable solvent such as acetic acid and treated with a suitable catalyst such as Pearlman""s catalyst under a positive pressure of hydrogen, as exemplified in Example 79. Compounds of formulae VIIA and VIIB may be made via conventional methods as exemplified in the Preparations section below, see for instance Preparation 52.
Method 9
Compounds of formulae IA and IB where R2 is CH2CH2OG, where G is 2-(hydroxymethyl)-5-pyrimidinyl can be made via reaction of the corresponding compounds of formula VIIIA or VIIIB 
with a suitable reducing agent such as sodium borohydride in a suitable solvent such as ethanol, as exemplified in Example 90. Compounds of formulae VIIIA and VIIIB may be made via conventional methods as exemplified in the synthetic sequence of the derivatives Examples 2, 3, 38 and Preparation 4 respectively.
It is to be understood that certain substances of the invention can be interconverted into certain other substances of the invention by standard methodology.
Where desired or necessary the compound of formula IA or IB is converted into a pharmaceutically or veterinarily acceptable salt thereof. A pharmaceutically or veterinarily acceptable salt of a compound of formula (I) may be conveniently be prepared by mixing together solutions of a compound of formula (I) and the desired acid or base, as appropriate. The salt may be precipitated from solution and collected by filtration, or may be collected by other means such as by evaporation of the solvent.
The compounds of the invention may be separated and purified by conventional methods.
The invention provides for a compound of the invention as defined above, for use as a medicament.
The invention also provides for the use of a substance of the invention as defined above, in the manufacture of a medicament for the treatment of restenosis, acute/chronic renal failure, pulmonary hypertension, systemic hypertension; benign prostatic hyperplasia, male erectile dysfunction, prostate cancer, metastatic bone cancer, congestive heart failure, stroke, subarachnoid haemorrhage, angina, atherosclerosis, cerebral and cardiac ischaemia, prevention of ischaemia/reperfusion injury (e.g. allografts), cyclosporin induced nephrotoxicity, glaucoma, radiocontrast nephropathy, diabetic neuropathy, allergy, restoration of organ perfusion in haemorrhagic shock, lipoprotein lipase related disorders, chronic obstructive pulmonary disease and hyaline membrane disease in newborn.
The invention also provides the use of a compound of the invention in the preparation of a medicament for the treatment of conditions mediated by endothelin, particularly endothelin-A. Also provided is a method of treatment of conditions mediated by endothelin, particularly endothelin-A, which comprises administering a therapeutically effective amount of a substance of the invention, to a patient in need of such treatment.
Reference to treatment herein includes prevention of undesirable conditions as well as alleviation or cure of said conditions.
The biological activity of the substances of the invention may be demonstrated as follows:
Dog Binding Assay
Competition between test substances and ligands binding to canine endothelin receptors is determined as follows:
Dog ET-A Binding Assay
50 xcexcl of a 500 pM solution of 125I-PD-151242 (Specific activity 2,000 Ci/mM) is mixed with 50 xcexcl samples of test substances (final concentrations in the range from 0.01-10,000 nM). 100 xcexcg of purified dog kidney homogenate is added in 150 xcexcl of the following buffer: 50 mM Tris, 10 mM MgCl2 and 0.05% Bovine Serum Albumen at pH 7.4. The solution is incubated at room temperature for 2 hours. After the incubation, the unbound ligand is separated from receptor bound ligand by filtration with a Brandel cell harvester, followed by 5 washes with buffer (Tris 50 mM, MgCl210 mM). Filter papers are counted for radioactivity and the Ki (an IC50 corrected for the dissociation constant and concentration of the ligand added) is determined for the concentration range tested.
Dog ET-B Binding Assay
50 xcexcl of a 100 pM solution of 125I-IRL-1620 (Specific activity 2,200 Ci/mM) is mixed with 50 xcexcl samples of test substances (final concentrations in the range from 0.01-10,000 nM). 50 xcexcg of purified Dog cerebellum homogenate is added in 150 xcexcl of the following buffer; 50 mM Tris, 10 mM MgCl2 and 0.05% Bovine Serum Albumen at pH 7.4. The solution is incubated at 30xc2x0 C. for 90 minutes. After the incubation, the unbound ligand is separated from receptor bound ligand by filtration with a Brandel cell harvester, followed by 5 washes with buffer (Tris 50 mM, MgCl2 10 mM). Filter papers are counted for radioactivity and the Ki (an IC50 corrected for the dissociation constant and concentration of the ligand added) is determined for the concentration range tested.
Human Binding Assay
Competition between test substances and 125I-ET-1 binding to human endothelin receptors is determined as follows.
Binding to ETA Receptors
25 xcexcl of a 30 pM solution of [125I]Tyr13 ET-1 (specific activity 2,200 Ci/mM) is mixed with 25 xcexcl samples of test substance (final concentrations in the range 0.1 nM-50,000 nM). 200 xcexcl of a solution containing cloned human ETA receptor (0.75 pmoles receptor protein/ml), 50 mM Tris, 0.5 mM CaCl2, 0.1% human serum albumen, 0.1% bacitracin, 0.05% Tween 20, pH 7.4 is added. The solution is mixed at 37xc2x0 C. for 2 hours. After the incubation, the unbound ligand is separated from receptor bound ligand by filtration with a Brandel cell harvester, followed by three washes of buffer. Filter papers are counted for radioactivity, and the IC50 (the concentration of test compound at which 50% of the radio-labelled compound is unbound) determined for the concentration range tested.
Binding to ETB Receptors
25 xcexcl of a 30 pM solution of [125I]Tyr13 ET-1 (specific activity 2,200 Ci/mM) is mixed with 25 xcexcl samples of test substance (final concentration 0.1 nM-50,000 nM). 200 xcexcl of a solution containing cloned human ETB receptor (0.25 pmoles receptor protein/ml), 50 mM Tris, 0.5 mM CaCl2, 0.1% human serum albumen, 0.1% bacitracin, 0.05% Tween 20, pH 7.4 is added. The solution is mixed at 37xc2x0 C. for 2 hours. After the incubation, the unbound ligand is separated from receptor bound ligand by filtration with a Brandel cell harvester, followed by three washes of buffer. Filter papers are counted for radio-activity, and the IC50 (the concentration of test compound at which 50% of the radio-labelled compound is unbound) determined for the concentration range tested.
The compounds of the present invention wee tested and found to have good affinity for endothelin receptors and to be selective for ETA over ETB.
The substances of the invention can be administered alone but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice. For example they can be administered orally in the form of tablets containing such excipients as starch or lactose or in capsules or ovules either alone or in admixture with excipients or in the form of elixirs, solutions or suspensions containing the substance in a liquid carrier, for example a vegetable oil, glycerine or water with a flavouring or colouring agent. They can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parental administration, they are best used as sterile aqueous solutions which may contain other substances, for example, enough glucose or salts to make the solution isotonic with blood. For parenteral administration the substance may also be administered as a solution or suspension in a suitable oil, for example polyethylene glycol, lecithin or sesame oil.
The compounds of the formula (I) may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
Substances of the invention may also be administered through inhalation of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane.
For oral or parenteral administration to human patients the daily dosage levels of substances of the invention will be from 0.01 to 30 mg/kg (in single or divided doses) and preferably will be in the range 0.01 to 5 mg/kg. Thus tablets will contain 1 mg to 0.4 g of substance for administration singly or two or more at a time, as appropriate. The above dosages are, of course only exemplary of the average case and there may be instances where higher or lower doses are merited, and such are within the scope of the invention.
Alternatively the substances of the invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder or in the form of a medicated plaster, patch or membrane. For example they may be incorporated in a cream containing an aqueous emulsion of polyethylene glycols or liquid paraffin. The compounds may also be administered intranasally.
For veterinary use although it is possible to administer a substance of the invention directly without any formulation, the substances are preferably employed in the form of a pharmaceutical or veterinary formulation comprising a pharmaceutically or veterinarily acceptable carrier, diluent or excipient and a substance of the invention. Such compositions will contain from 0.1 percent by weight to 90.0 percent by weight of the active ingredient.
The methods by which the compounds may be administered include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo or powder formulation or, alternatively, they can be administered by injection (e.g. subcutaneously, intramuscularly or intravenously), or as an implant.
Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. Thus capsules, boluses or tablets may be prepared by mixing the active ingredient with a suitable finely divided diluent or carrier additionally containing a disintegrating agent and/or binder such as starch, lactose, talc or magnesium stearate, etc. Oral drenches are prepared by dissolving or suspending the active ingredient in a suitable medium. Pour-on or spot-on formulations may be prepared by dissolving the active ingredient in an acceptable liquid carrier vehicle such as butyl digol, liquid paraffin or a non-volatile ester, optionally with the addition of a volatile component such as propan-2-ol.
Alternatively, pour-on, spot-on or spray formulations can be prepared by encapsulation, to leave a residue of active agent on the surface of the animal. Injectable formulations may be prepared in the form of a sterile solution which may contain other substances, for example enough salts or glucose to make the solution isotonic with blood. Acceptable liquid carriers include vegetable oils such as sesame oil, glycerides such as triacetin, esters such as benzyl benzoate, isopropyl myristrate and fatty acid derivatives of propylene glycol, as well as organic solvents such as pyrrolidin-2-one and glycerol formal. The formulations are prepared by dissolving or suspending the active ingredient in the liquid carrier such that the final formulation contains from 0.1 to 10% by weight of the active ingredient.
These formulations will vary with regard to the weight of active substance contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal. For parenteral, topical and oral administration, typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is 0.1 to 10 mg per kg.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg, more usually about 5 to about 300 mg, of the active ingredient. The term xe2x80x9cunit dosage formxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
As an alternative for veterinary use the substances may be administered with animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
Thus, according to a further aspect of the invention, there are provided pharmaceutical formulations comprising a substance of the invention, as defined above, and a pharmaceutically-acceptable adjuvant, diluent or carrier.